Clinically, ischemic stroke is recognized as a sexually dimorphic disease. Most international databases consistently demonstrate that women enjoy a lower stroke incidence relative to men until advanced age. Reproductive hormones contribute to such differences in male and female pathobiology, as a wealth of data show that estrogens and progestins alter neuronal survival after injury both in vivo and in vitro. However, it is becoming increasingly evident that the hormonal environment does not fully account for ischemic sexual dimorphism. Tissue damage and functional outcome after ischemic damage are shaped by biologic sex in addition to the hormonal milieu. Sex differences in stroke have been well documented in pediatric populations;both stroke incidence and stroke-related disability are higher in boys despite equivalent levels of circulating hormones. Similar findings are seen in experimental models of neonatal hypoxic- ischemic encephalopathy). The most convincing evidence for intrinsic biological differences in stroke sensitivity between the sexes is that sex-specificity can also be modeled in cell culture when sex steroids are removed from the media. One of the new concepts that must be considered is that stroke operates in a different genetic background in females (XX) and males (XY). We hypothesize that basic mechanisms of ischemic cell death differ in males and females based on the chromosomal complement. We will test this hypothesis by examining outcome in two recently developed mouse strains that have a single X chromosome (X0) secondary to meiotic non-disjunction. The 39, XO mice will be compared to 40, XX and 40 XY littermates to provide data on X-linked gene dosage effects. Key X-linked cell death proteins (X linked inhibitor of apoptosis (XIAP) and Apoptosis Inducing Factor (AIF)) will be evaluated in XX, XO and XY mice to determine the contribution of the second X chromosome to ischemic sensitivity. PUBLIC HEALTH RELEVANCE: Over the past five years, data are emerging that basic cell death mechanisms activated after ischemic insults are strongly influenced by biological sex. The contribution of the sex chromosomes (XX vs. XY) to stroke sensitivity is not known, but could account in part for the dramatic sex differences seen in stroke incidence and outcome. We hypothesize that basic mechanisms of ischemic cell death differ in males and females based on the chromosomal complement. We will evaluate stroke outcome in mice with a single X chromosome (XO) secondary to meiotic non-disjunction. The 39, XO mice will be compared to 40, XX and 40, XY littermates to provide data on X-linked gene dosage effects.